The Biopharmaceutical Development Program (BDP) supports development, manufacturing, and testing of new concepts in cancer therapeutics based on biological agents and biological response modifiers. Located at the NCI-Frederick campus, the BDP uses leading-edge technologies for development of monoclonal antibodies, cytokines, immunotoxins and other recombinant proteins, peptide and DNA vaccines, virus vaccines and targeted cytolytic viruses, gene therapy products, and other biological agents. The BDP maintains Current Good Manufacturing Practices (CGMP)-compliant facilities that provide complete support from evaluation of manufacturing feasibility through process development and clinical manufacturing with all required regulatory documentation for proof of concept clinical studies. BDP is a major component of the research grant and contract program of the Biological Resources Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, of the National Cancer Institute (BRB, DTP, DCTD, NCI). During the 2008 Fiscal Year, the BDP released 22 manufacturing lots to support clinical trials or toxicological studies, and performed QC stability studies to support more than 40 other lots still in use. With a staff of 100 highly trained and experienced personnel, the BDP has undertaken over 100 projects since its inception, and over 60 of these have gone into clinical trials. BDP facilities are designed to be highly flexible, enabling work on multiple projects for a variety of different therapies. An innovative, dynamic program, the BDP mission is to concentrate on products that are in early development, beginning with demonstrating product feasibility, through to production of Phase I/II clinical supplies and complete testing. In support of an NCI Immunotherapy Workshop initiative, BDP established a new cGMP manufacturing process for Interleukin-15. IL-15 from BDP is now in toxicological studies for the first clinical trial that is expected to start in FY09. In FY08, BDP also supported QC re-certification of Interleukin-12 that had been donated by the original manufacturer. IL-12 will be made available through a CTEP mechanism to qualified investigators for a number of new cancer immunotherapy and vaccine trials. Ad-CCL-21, another Immunotherapy agent manufactured by BDP, was shipped to two institutions for vaccine trials using chemokine gene-modified dendritic cells in advanced non-small lung cancer and malignant melanoma. In FY08, BDP released a clinical lot of Ad5-SSTR/TK.RGD a tropism modified adenovirus vector for an initial clinical trial in patients with ovarian cancer. Manufacturing and testing were completed for rRp450, a recombinant herpes virus, and an IND will be filed for treatment of patients with liver metastases. Ad-Delta-24-RGD is now in a clinical trial in patients with ovarian cancer and another trial in glioma. A second trial in glioma is in the process of regulatory filing. A BDP product that was released before FY08 is MR1-1, an immunotoxin that targets glioma. The first two patients were treated with MR1-1 during FY08. AdAFP and two plasmids targeting alpha-feto protein (AFP) entered a phase I clinical trial in hepatocellular carcinoma, and a second trial is pending at another institution. Ad5/3delta-24 was released and toxicological studies are underway for a Phase I clinical trial in ovarian cancer. During FY08, STAT3 decoy, an oligonucleotide targeting the STAT3 pathway of head and neck cancer entered a Phasezero clinical trial. A previously released measles-based oncolytic virus, MV-NIS, that is already in a Phase I trial for multiple myeloma, entered a new Phase I clinical trial in ovarian cancer. The 11-1F4 project is an earlier RAID project for development of a chimeric antibody targeting amyloid deposits. In FY08, interesting imaging of amyloid deposits was achieved in initial patients entered on an imaging study using murine-11-1F4. The continued results in this study are being followed for leads in this challenging disease. Other BDP activities in FY08 supported development of many other new agents for clinical trials in patients with prostate cancer, ovarian cancer, glioma, cervical cancer, and lymphoma, among other cancer indications. Under the Economy in Government Act, BDP also performed reimbursed manufacturing activities for other institutes in support of clinical trials in Type I Diabetes and Malaria Vaccines. In these projects, BDP developed new expertise that will be directly applicable to projects coming into the BDP cancer pipeline. BDP saw some of its earlier products reaching FY08 clinical milestones beyond early Phase I/II studies. During FY08, BDP released several lots of HA-22, an immunotoxin in clinical trials in non-Hodgkins lymphoma. A commercial company has licensed this agent and will perform further manufacturing at their facilities. Hu14.18-IL2, a cytokineantibody fusion protein that targets the GD-2 antigen on malignant melanoma and pediatric neuroblastoma is a legacy BDP project for which multiple clinical lots have been manufactured. During FY08, Hu14.18-IL-2 entered combination clinical trials with an anti-angiogenesis agent, in melanoma patients with minimal residual disease. BDP is supporting technology transfer for further development at the commercial company holding the intellectual property. Another legacy BDP project is a patient-specific Id vaccine for lymphoma that was licensed and taken over by a commercial company after BDP made over 100 patient-specific products for several early studies. In FY08, this vaccine completed a Phase III clinical trial in non-Hodgkin's lymphoma, and the company announced plans to discuss results with FDA. FDA requires testing to demonstrate product stability during the planned administration of many BDP agents, because biologicals can be susceptible to degradation over time in interactions with various fluids, even plastic intravenous tubing. In FY08, BDP performed an increasing number of point-of-use studies for a variety of products, including monoclonal antibodies and viruses. These studies require a number of tests to validate the accuracy of these critical assessments of product quality during administration. In addition, BDP QC staff are collaborating directly with FDA investigators to improve in vitro adventitious virus assays for oncolytic viruses, a challenging safety issue in this field. In FY 08, BDP made its established systems and experienced personnel available to provide assistance to other academic and government programs. BDP hosted visitors from outside U.S. institutions, other government agencies, and foreign countries, providing training on establishing other programs similar to the BDP. In tours and training sessions of BDP manufacturing facilities, outside investigators were presented an overview of how BDP Quality Systems translate Good Manufacturing Practice (GMP) regulations into practice for a Phase I/II product. The BDP scientific staff members continued to be active within the extramural community, serving on academic faculties and advisory committees, and presenting scientific findings at national and international meetings.